1. Field of the Invention
The present invention is directed to a novel process for preparing heteroaryl and unsaturated heterocycloalkylmagnesium reagents that are useful in the synthesis of a variety of pharmaceuticals, in particular certain cysteine protease inhibitors.
2. State of the Art
Heteroaryl and unsaturated heterocycloalkylmagnesium reagents are useful in the synthesis of a variety of pharmaceuticals, such as renin inhibitors and cysteine protease inhibitors. For example, heteroarylmagnesium reagents are used in the synthesis of 1-hydroxy-1-(heteroaryl or unsaturated heterocycloalkyl)-2-N-protected-aminoethyl intermediates which are then used in the synthesis of a number of peptidic pharmaceutically active agents (see EP 0376012 which discloses the use of 1-hydroxy-1-(heteroaryl)-2-aminoethyl in the synthesis of renin inhibitors and PCT Application Publication No. WO 00/55144 and Ohmoto, K. et. al., J. Med. Chem. 2001, 44, 1268 which disclose the use of 1-hydroxy-1-(heteroaryl or heterocycloalkyl)-2-aminoethyl in the synthesis of protease inhibitors). At present, 1-hydroxy-1-(heteroaryl)-2-N-protected-aminoethyl intermediates used are prepared by reacting an aldehyde with a heteroarylmagnesium reagent or by assembly of the heterocyclic/heteroaryl ring. The heteroarylmagnesium reagent used in this process is prepared by first treating a heteroaryl with an organolithium reagent and then converting the resulting lithiated species into a Grignard reagent under transmetallation reaction conditions. The drawbacks of these procedures are that they require very low reaction temperatures, typically −78° C., or are not the most economical or expedient route.
In order to avoid low temperature chemistry, the heteroarylmagnesium reagent can be prepared by reacting the corresponding heteroaryl halide with magnesium turnings in the presence of an initiation mixture containing ethyl bromide and iodine crystals. The drawback of this procedure is that the initiation of the reaction is very unpredictable and the reaction is highly exothermic and hence requires appropriate set up to keep the reaction temperature under control. Additionally, this method can be subject to undesirable side reactions, such as Wurtz coupling. These drawbacks make the use of heteroaryl or unsaturated heterocycloalkylmagnesium reagents unattractive for large-scale synthesis of pharmaceuticals.
Accordingly, there is a need for a synthetic process that would be amenable to large-scale synthesis of these compounds without the limitations discussed above. The present invention fulfills this and related needs.